Claims:

1. A medical device comprising:a nitric oxide (NO)-releasing,
biocompatible, biodegradable polymer having the general structure of
formula 7: ##STR00035## wherein m is 0 or 1; n is 0 to 10; p is 0 or 1; o
is 0 to 10, R1, R2, R5, R6 is each individually
hydrogen, a C1-6 alkyl group, a diazeniumdiolate, if m or p is 0,
R3, R4, R7 R8 is individually hydrogen or a
diazeniumdiolate, if m or p is 1; and wherein at least one of R1-8
must be a diazeniumdiolate.

6. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
8a: ##STR00036## wherein a is an integer from 1 to about 20,000; b is an
integer from about 1 to about 100 and the sum of a and b is at least 2;
and A1-A5 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-5 must be a
diazeniumdiolate.

7. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
9a: ##STR00037## wherein a is an integer from 1 to about 20,000; b is an
integer from about 1 to about 100 and the sum of a and b is at least 2;
and A1-A6 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-6 must be a
diazeniumdiolate.

8. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
10a: ##STR00038## wherein a is an integer from 1 to about 20,000; and
A1-A4 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-4 must be a
diazeniumdiolate.

9. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
11a: ##STR00039## wherein a is an integer from 1 to about 20,000; b is an
integer from about 1 to about 100 and the sum of a and b is at least 2;
and A1-A5 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-5 must be a
diazeniumdiolate.

10. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
12a: ##STR00040## wherein a is an integer from 1 to about 20,000; and
A1-A4 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-4 must be a
diazeniumdiolate.

11. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
13a: ##STR00041## wherein a is an integer from 1 to about 20,000; b is an
integer from about 1 to about 100 and the sum of a and b is at least 2;
and A1-A6 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-6 must be a
diazeniumdiolate.

12. A medical device comprising:a nitric oxide (NO)-releasing,
biocompatible, biodegradable polymer having at least one diazeniumdiolate
group bound to a carbon adjacent to a carbonyl group.

17. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
8a: ##STR00042## wherein a is an integer from 1 to about 20,000; b is an
integer from about 1 to about 100 and the sum of a and b is at least 2;
and A1-A5 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-5 must be a
diazeniumdiolate.

18. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
9a: ##STR00043## wherein a is an integer from 1 to about 20,000; b is an
integer from about 1 to about 100 and the sum of a and b is at least 2;
and A1-A6 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-6 must be a
diazeniumdiolate.

19. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
10a: ##STR00044## wherein a is an integer from 1 to about 20,000; and
A1-A4 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-4 must be a
diazeniumdiolate.

20. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
11a: ##STR00045## wherein a is an integer from 1 to about 20,000; b is an
integer from about 1 to about 100 and the sum of a and b is at least 2;
and A1-A5 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-5 must be a
diazeniumdiolate.

21. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
12a: ##STR00046## wherein a is an integer from 1 to about 20,000; and
A1-A4 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-4 must be a
diazeniumdiolate.

22. The medical device according to claim 1 wherein the biodegradable
polymer comprises a compound according to a general structure of Formula
13a: ##STR00047## wherein a is an integer from 1 to about 20,000; b is an
integer from about 1 to about 100 and the sum of a and b is at least 2;
and A1-A6 are individually hydrogen, C1-6 alkyl or a
diazeniumdiolate group, and at least one of A1-6 must be a
diazeniumdiolate.

23. A vascular stent comprising:a NO-releasing, biocompatible,
biodegradable polymer having at least one diazeniumdiolate group bound to
a carbon adjacent to a carbonyl groupfurther comprising the general
structure of formula 7: ##STR00048## wherein m is 0 or 1; n is 0 to 10; p
is 0 or 1; o is 0 to 10, R1, R2, R5, R6 is each
individually hydrogen, a C1-6 alkyl group, a diazeniumdiolate, if m
or p is 0. R3, R4, R7 R8 is individually hydrogen or
a diazeniumdiolate, if m or p is 1; wherein at least one of R1-8
must be a diazeniumdiolate; andwherein said biodegradable polymer further
comprises zotarolimus.

Description:

[0002]Nitric oxide (NO) is a simple diatomic molecule that plays a diverse
and complex role in cellular physiology. Less than 25 years ago NO was
primarily considered a smog component formed during the combustion of
fossil fuels mixed with air. However, as a result of the pioneering work
of Ferid Murad et al. it is now known that NO is a powerful signaling
compound and cytotoxic/cytostatic agent found in nearly every tissue
including endothelial cells, neural cells and macrophages. Mammalian
cells synthesize NO using a two step enzymatic process that oxidizes
L-arginine to N-ω-hydroxy-L-arginine, which is then converted into
L-citrulline and an uncharged NO free radical. Three different nitric
oxide synthase enzymes regulate NO production. Neuronal nitric oxide
synthase (NOSI, or nNOS) is formed within neuronal tissue and plays an
essential role in neurotransmission; endothelial nitric oxide synthase
(NOS3 or eNOS), is secreted by endothelial cells and induces
vasodilatation; inducible nitric oxide synthase (NOS2 or iNOS) is
principally found in macrophages, hepatocytes and chondrocytes and is
associated with immune cytotoxicity.

[0003]Neuronal NOS and eNOS are constitutive enzymes that regulate the
rapid, short-term release of small amounts of NO. These minute amounts NO
activate guanylate cyclase which elevates cyclic guanosine monophosphate
(cGMP) concentrations which in turn increase intracellular Ca2+
levels. Increased intracellular Ca2+ concentrations result in smooth
muscle relaxation which accounts for the vasodilating effects of NO.
Inducible NOS is responsible for the sustained release of larger amounts
of NO and is activated by extracellular factors including endotoxins and
cytokines. These higher NO levels play a key role in cellular immunity.

[0004]Medical research, especially in the fields of vascular surgery and
interventional cardiology, is rapidly discovering therapeutic
applications for NO. Procedures used to clear blocked arteries such as
percutaneous transluminal coronary angioplasty (PTCA) (also known as
balloon angioplasty) and atherectomy and/or stent placement can result in
vessel wall injury at the site of balloon expansion or stent deployment.
In response to this injury a complex multi-factorial process known as
restenosis can occur whereby the previously opened vessel lumen narrows
and becomes re-occluded. Restenosis is initiated when thrombocytes
(platelets) migrating to the injury site release mitogens into the
injured endothelium. Thrombocytes begin to aggregate and adhere to the
injury site initiating thrombogenesis, or clot formation. As a result,
the previously opened lumen begins to narrow as thrombocytes and fibrin
collect on the vessel wall. In a more frequently encountered mechanism of
restenosis, the mitogens secreted by activated thrombocytes adhering to
the vessel wall stimulate overproliferation of vascular smooth muscle
cells during the healing process, restricting or occluding the injured
vessel lumen. The resulting neointimal hyperplasia is the major cause of
a stent restenosis.

[0005]Recently, NO has been shown to significantly reduce thrombocyte
aggregation and adhesion; this combined with NO's direct
cytotoxic/cytostatic properties may significantly reduce vascular smooth
muscle cell proliferation and help prevent restenosis. Thrombocyte
aggregation occurs within minutes following the initial vascular insult
and once the cascade of events leading to restenosis is initiated,
irreparable damage can result. Moreover, the risk of thrombogenesis and
restenosis persists until the endothelium lining the vessel lumen has
been repaired. Therefore, it is essential that NO, or any anti-restenotic
agent, reach the injury site immediately.

[0006]One approach for providing a therapeutic level of NO at an injury
site is to increase systemic NO levels prophylactically. This can be
accomplished by stimulating endogenous NO production or using exogenous
NO sources. Methods to regulate endogenous NO release have primarily
focused on activation of synthetic pathways using excess amounts of NO
precursors like L-arginine, or increasing expression of nitric oxide
synthase (NOS) using gene therapy. U.S. Pat. Nos. 5,945,452, 5,891,459
and 5,428,070 describe sustained NO elevation using orally administrated
L-arginine and/or L-lysine. However, these methods have not been proven
effective in preventing restenosis. Regulating endogenously expressed NO
using gene therapy techniques remains highly experimental and has not yet
proven safe and effective. U.S. Pat. Nos. 5,268,465, 5,468,630 and
5,658,565, describe various gene therapy approaches.

[0007]Exogenous NO sources such as pure NO gas are highly toxic,
short-lived and relatively insoluble in physiological fluids.
Consequently, systemic exogenous NO delivery is generally accomplished
using organic nitrate prodrugs such as nitroglycerin tablets, intravenous
suspensions, sprays and transdermal patches. The human body rapidly
converts nitroglycerin into NO; however, enzyme levels and co-factors
required to activate the prodrug are rapidly depleted, resulting in drug
tolerance. Moreover, systemic NO administration can have devastating side
effects including hypotension and free radical cell damage. Therefore,
using organic nitrate prodrugs to maintain systemic anti-restenotic
therapeutic blood levels is not currently possible.

[0008]Therefore, considerable attention has been focused on localized, or
site specific, NO delivery to ameliorate the disadvantages associated
with systemic prophylaxis. Implantable medical devices and/or local gene
therapy techniques including medical devices coated with NO-releasing
compounds, or vectors that deliver NOS genes to target cells, have been
evaluated. Like their systemic counterparts, gene therapy techniques for
the localized NO delivery have not been proven safe and effective. There
are still significant technical hurdles and safety concerns that must be
overcome before site-specific NOS gene delivery will become a reality.

[0009]However, significant progress has been made in the field of
localized exogenous NO application. To be effective at preventing
restenosis an inhibitory therapeutic such as NO must be administered for
a sustained period at therapeutic levels. Consequently, any NO-releasing
medical device used to treat restenosis must be suitable for
implantation. An ideal candidate device is the vascular stent. Therefore,
a stent that safely provides therapeutically effective amounts of NO to a
precise location would represent a significant advance in restenosis
treatment and prevention.

[0010]Nitric Oxide releasing compounds suitable for in vivo applications
have been developed by a number of investigators. As early as 1960 it was
demonstrated that nitric oxide gas could be reacted with amines, for
example, diethylamine, to form NO-releasing anions having the following
general formula R--R'N--N(O)NO. Salts of these compounds could
spontaneously decompose and release NO in solution.

[0011]Nitric Oxide releasing compounds with sufficient stability at body
temperatures to be useful as therapeutics were ultimately developed by
Keefer et al. as described in U.S. Pat. Nos. 4,954,526, 5,039,705,
5,155,137, 5,212,204, 5,250,550, 5,366,997, 5,405,919, 5,525,357 and
5,650,447 all of which are herein incorporated by reference.

[0012]The in vivo half-life of NO, however, is limited, causing
difficulties in delivering NO to the intended area. Therefore
NO-releasing compounds which can produce extended release of NO are
needed. Several exemplary NO-releasing compounds have been developed for
this purpose, including for example a NO donating aspirin derivative,
amyl nitrite and isosorbide dinitrate. Additionally, biocompatible
polymers having NO adducts (see, for example, U.S. Patent Publications
2006/0008529 and 2004/0037836) that release NO in a controlled manner
have been reported.

[0013]Secondary amines have the ability to bind two NO molecules and
release them in an aqueous environment. The general structure of an
exemplary secondary amine capable of binding two NO molecules is depicted
below in Formula 1, referred to hereinafter a diazeniumdiolate, (wherein
M is a counterion, and can be a metal, with the appropriate charge, or a
proton and wherein R is a generic notation for organic and inorganic
chemical groups). Exposing secondary amines to basic conditions while
incorporating NO gas under high pressure leads to the formation of
nitrogen-based diazeniumdiolates.

##STR00001##

[0014]However, nitrogen-based diazeniumdiolate-containing polymers cannot
be formulated as bioabsorbable polymers due to the possible breakdown of
the nitrogen-based diazeniumdiolate moiety into nitrosamines which are
carcinogens and irritants. Therefore bioabsorbable NO-donating polymers
that do not incorporate nitrogen-based diazeniumdiolates are needed.
Described herein are carbon-based NO-donating polymers.

SUMMARY OF THE INVENTION

[0015]The present description relates to bioabsorbable carbon based
diazeniumdiolate (C-based) nitric oxide (NO) donating polymers suitable
for forming and coating medical devices. The polymers can have polyester
and polyether backbones and are comprised of monomers including, but not
limited to, ε-caprolactone, polyethylene glycol (PEG),
trimethylene carbonate, lactide, glycolide and their derivatives.
Structural integrity and mechanical durability are provided through the
use of lactide and glycolide. Elasticity is provided by caprolactone and
trimethylene carbonate. Varying the monomer ratios allows the
practitioner to fine tune, or modify, the properties of the C-based NO
releasing polymer to control physical properties. The polymers contain
acidic carbon bonded hydrogens that upon treatment with base are
de-protonated, enabling the resulting carbanion to react with individual
NO molecules producing C-based diazeniumdiolates. The polymers can also
be suitable for manufacturing implantable medical devices. In one
embodiment, a medical device is manufactured from a bioabsorbable
biocompatible polymer. In another embodiment, the bioabsorbable
biocompatible polymer is provided as a coating on a medical device. In
yet another embodiment, a drug is provided in the bioabsorbable
biocompatible polymer medical device or coating.

[0016]A medical device is described herein comprising: a nitric oxide
(NO)-releasing, biocompatible, biodegradable polymer having the general
structure of formula 7:

##STR00002##

wherein m is 0 or 1; n is 0 to 10; p is 0 or 1; o is 0 to 10, R1,
R2, R5, R6 is each individually hydrogen, a C1-6
alkyl group, a diazeniumdiolate, if m or p is 0. R3, R4,
R7 R8 is individually hydrogen or a diazeniumdiolate, if m or p
is 1; and wherein at least one of R1-8 must be a diazeniumdiolate.
In one embodiment, the polymer comprises monomers selected from the group
consisting of ε-caprolactone, trimethylene carbonate,
2-acetylbutyrolactone, Formula 10, 4-tert-butyl caprolactone, N-acetyl
caprolactone, cyclohexyl caprolactones, lactide, glycolide, p-dioxanone,
β-butyrolactones, γ-butyrolactones, γ-valerolactone,
δ-valerolactone and phosphate ester.

[0017]In one embodiment, the diazeniumdiolate group is further stabilized
by a counterion selected from the group consisting of sodium, potassium,
a proton, and lithium.

[0020]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 8a:

##STR00003##

wherein a is an integer from 1 to about 20,000; b is an integer from about
1 to about 100 and the sum of a and b is at least 2; and A1-A5
are individually hydrogen, C1-6 alkyl or a diazeniumdiolate group,
and at least one of A1-5 must be a diazeniumdiolate.

[0021]In another embodiment, the biodegradable polymer comprises a
compound according to a general structure of Formula 9a:

##STR00004##

wherein a is an integer from 1 to about 20,000; b is an integer from about
1 to about 100 and the sum of a and b is at least 2; and A1-A6
are individually hydrogen, C1-6 alkyl or a diazeniumdiolate group,
and at least one of A1-6 must be a diazeniumdiolate.

[0022]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 10a:

##STR00005##

wherein a is an integer from 1 to about 20,000; and A1-A4 are
individually hydrogen, C1-6 alkyl or a diazeniumdiolate group, and
at least one of A1-4 must be a diazeniumdiolate.

[0023]In one embodiment, biodegradable polymer comprises a compound
according to a general structure of Formula 11a:

##STR00006##

wherein a is an integer from 1 to about 20,000; b is an integer from about
1 to about 100 and the sum of a and b is at least 2; and A1-A5
are individually hydrogen, C1-6 alkyl or a diazeniumdiolate group,
and at least one of A1-5 must be a diazeniumdiolate.

[0024]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 12a:

##STR00007##

wherein a is an integer from 1 to about 20,000; and A1-A4 are
individually hydrogen, C1-6 alkyl or a diazeniumdiolate group, and
at least one of A1-4 must be a diazeniumdiolate.

[0025]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 13a:

##STR00008##

wherein a is an integer from 1 to about 20,000; b is an integer from about
1 to about 100 and the sum of a and b is at least 2; and A1-A6
are individually hydrogen, C1-6 alkyl or a diazeniumdiolate group,
and at least one of A1-6 must be a diazeniumdiolate.

[0026]In one embodiment, a medical device is described comprising: a
nitric oxide (NO)-releasing, biocompatible, biodegradable polymer having
at least one diazeniumdiolate group bound to a carbon adjacent to a
carbonyl group. In another embodiment, the polymer comprises monomers
selected from the group consisting of ε-caprolactone,
trimethylene carbonate, 2-acetylbutyrolactone, Formula 10, 4-tert-butyl
caprolactone, N-acetyl caprolactone, cyclohexyl caprolactones, lactide,
glycolide, p-dioxanone, β-butyrolactones, γ-butyrolactones,
γ-valerolactone, δ-valerolactone and phosphate ester. In
another embodiment, the diazeniumdiolate group is further stabilized by a
counterion selected from the group consisting of sodium, potassium, a
proton, and lithium.

[0029]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 8a:

##STR00009##

wherein a is an integer from 1 to about 20,000; b is an integer from about
1 to about 100 and the sum of a and b is at least 2; and A1-A5
are individually hydrogen, C1-6 alkyl or a diazeniumdiolate group,
and at least one of A1-5 must be a diazeniumdiolate.

[0030]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 9a:

##STR00010##

wherein a is an integer from 1 to about 20,000; b is an integer from about
1 to about 100 and the sum of a and b is at least 2; and A1-A6
are individually hydrogen, C1-6 alkyl or a diazeniumdiolate group,
and at least one of A1-6 must be a diazeniumdiolate.

[0031]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 10a:

##STR00011##

wherein a is an integer from 1 to about 20,000; and A1-A4 are
individually hydrogen, C1-6 alkyl or a diazeniumdiolate group, and
at least one of A1-4 must be a diazeniumdiolate.

[0032]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 11a:

##STR00012##

wherein a is an integer from 1 to about 20,000; b is an integer from about
1 to about 100 and the sum of a and b is at least 2; and A1-A5
are individually hydrogen, C1-6 alkyl or a diazeniumdiolate group,
and at least one of A1-5 must be a diazeniumdiolate.

[0033]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 12a:

##STR00013##

wherein a is an integer from 1 to about 20,000; and A1-A4 are
individually hydrogen, C1-6 alkyl or a diazeniumdiolate group, and
at least one of A1-4 must be a diazeniumdiolate.

[0034]In one embodiment, the biodegradable polymer comprises a compound
according to a general structure of Formula 13a:

##STR00014##

wherein a is an integer from 1 to about 20,000; b is an integer from about
1 to about 100 and the sum of a and b is at least 2; and A1-A6
are individually hydrogen, C1-6 alkyl or a diazeniumdiolate group,
and at least one of A1-6 must be a diazeniumdiolate.

[0035]In one embodiment, a vascular stent is described comprising:
comprising a NO-releasing, biocompatible, biodegradable polymer having at
least one diazeniumdiolate group bound to a carbon adjacent to a carbonyl
group further comprising the general structure of formula 7:

##STR00015##

wherein m is 0 or 1; n is 0 to 10; p is 0 or 1; o is 0 to 10, R1,
R2, R5, R6 is each individually hydrogen, a C1-6
alkyl group, a diazeniumdiolate, if m or p is 0. R3, R4,
R7 R8 is individually hydrogen or a diazeniumdiolate, if m or p
is 1; wherein at least one of R1-8 must be a diazeniumdiolate; and
wherein said biodegradable polymer further comprises zotarolimus.

Definition of Terms

[0036]Prior to setting forth the invention, it may be helpful to an
understanding thereof to set forth definitions of certain terms that will
be used hereinafter:

[0037]Lactide: As used herein, lactide refers to
3,6-dimethyl-1,4-dioxane-2,5-dione (Formula 2). More commonly lactide is
also referred to herein as the heterodimer of R and S forms of lactic
acid, the homodimer of the S form of lactic acid and the homodimer of the
R form of lactic acid. Lactic acid and lactide are used interchangeably
herein. The term dimer is well known to those ordinarily skilled in the
art.

##STR00016##

[0038]Glycolide: As used herein, glycolide refers to a molecule having the
general structure of Formula 3.

##STR00017##

[0039]4-tert-butyl caprolactone: As used herein 4-tert-butyl caprolactone
refers to a molecule having the general structure of Formula 4.

##STR00018##

[0040]N-acetyl caprolactone: As used herein N-acetyl caprolactone refers
to a molecule having the general structure of Formula 5.

##STR00019##

[0041]Backbone: As used here in "backbone" refers to the main chain of a
polymer or copolymer. A "polyester backbone" as used herein refers to the
main chain of a bioabsorbable polymer comprising ester linkages. A
"polyether backbone" as used herein refers to the main chain of a
bioabsorbable polymer comprising ether linkages. An exemplary polyether
is polyethylene glycol (PEG).

[0042]Bioabsorbable: As used herein "bioabsorbable" refers to a polymeric
composition that is biocompatible and subject to being broken down in
vivo through the action of normal biochemical pathways. From time-to-time
bioabsorbable and biodegradable may be used interchangeably, however they
are not coextensive. Biodegradable polymers may or may not be reabsorbed
into surrounding tissues, however all bioabsorbable polymers are
considered biodegradable.

[0043]Biocompatible: As used herein "biocompatible" shall mean any
material that does not cause injury or death to the animal or induce an
adverse reaction in an animal when placed in intimate contact with the
animal's tissues. Adverse reactions include inflammation, infection,
fibrotic tissue formation, cell death, or thrombosis.

[0044]Copolymer: As used here in a "copolymer" will be defined as a
macromolecule produced by the simultaneous or step-wise polymerization of
two or more dissimilar units such as monomers. Copolymer shall include
bipolymers (two dissimilar units), terpolymers (three dissimilar units),
etc.

[0045]Controlled release: As used herein "controlled release" refers to
the release of a bioactive compound from a medical device surface at a
predetermined rate. Controlled release implies that the bioactive
compound does not come off the medical device surface sporadically in an
unpredictable fashion and does not "burst" off of the device upon contact
with a biological environment (also referred to herein a first order
kinetics) unless specifically intended to do so. However, the term
"controlled release" as used herein does not preclude a "burst
phenomenon" associated with deployment. In some embodiments, an initial
burst of drug may be desirable followed by a more gradual release
thereafter. The release rate may be steady state (commonly referred to as
"timed release" or zero order kinetics), that is the drug is released in
even amounts over a predetermined time (with or without an initial burst
phase) or may be a gradient release. A gradient release implies that the
concentration of drug released from the device surface changes over time.

[0047]Exemplary FKBP 12 binding compounds include sirolimus (rapamycin),
tacrolimus (FK506), everolimus (certican or RAD-001), temsirolimus
(CCI-779 or amorphous rapamycin 42-ester with
3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid) and zotarolimus
(ABT-578). Additionally, other rapamycin hydroxyesters may be used in
combination with the polymers.

[0048]Ductility: As used herein "ductility, or ductile" is a polymer
attribute characterized by the polymer's resistance to fracture or
cracking when folded, stressed or strained at operating temperatures.
When used in reference to the polymer coating compositions the normal
operating temperature for the coating will be between room temperature
and body temperature or approximately between 15° C. and
40° C. Polymer durability in a defined environment is often a
function of its elasticity/ductility.

[0049]Functional Side Chain: As used herein "functional side chain"
encompasses a first chemical constituent(s) typically capable of binding
to a second chemical constituent(s), wherein the first chemical
constituent modifies a chemical or physical characteristic of the second
chemical constituent. Functional groups associated with the functional
side chains include vinyl groups, hydroxyl groups, oxo groups, carboxyl
groups, thiol groups, amino groups, phosphate groups and others known to
those skilled in the art and as depicted in the present specification and
claims.

[0050]Glass Transition Temperature (Tg): As used herein glass
transition temperature (Tg) refers to a temperature wherein a
polymer structurally transitions from a elastic pliable state to a rigid
and brittle state.

[0051]Hydrophilic: As used herein in reference to the bioactive agent, the
term "hydrophilic" refers to a bioactive agent that has solubility in
water of more than 200 micrograms per milliliter.

[0052]Hydrophobic: As used herein in reference to the bioactive agent the
term "hydrophobic" refers to a bioactive agent that has solubility in
water of no more than 200 micrograms per milliliter.

[0053]Mn: As used herein Mn refers to number-average molecular
weight. Mathematically it is represented by the following formula:

[0054]Mw: As used herein Mw refers to weight average molecular
weight that is the average weight that a given polymer may have.
Mathematically it is represented by the following formula:

Mw=Σi Ni Mi2/Σi Ni Mi,
wherein Ni is the number of molecules whose weight is Mi.

DETAILED DESCRIPTION OF THE INVENTION

[0055]Disclosed herein are bioabsorbable carbon-based (C-based) nitric
oxide (NO)-donating polymers suitable for forming and coating medical
devices. The polymers can have polyester and polyether backbones and may
be comprised of hydrophilic and hydrophobic monomers.

[0056]As used herein, the terms "carbon-based" and "C-based" refer to
molecules having the general structure of Formula 6 wherein the
NO-donating groups, diazeniumdiolates are bound to carbon atoms. The
carbon atoms binding the diazeniumdiolate group are the alpha carbons
adjacent to carbonyl carbons. The carbonyl groups can be incorporated
into the polymer backbone, can exist on a pendant group attached to the
polymer backbone or can exist as a product of the polymer synthesis.

[0057]The carbonyl group increases the acidity of the alpha carbon(s) to
enable the deprotonation and diazeniumdiolation. In Formula 6, M may be a
counter ion including, but not limited to, lithium, sodium, potassium and
a proton; the carbon is an alpha carbon either on a pendent group or on
the polymer backbone itself. The purpose of the counter ion is to
stabilize the diazeniumdiolate group.

[0059]A generic structure for the diazeniumdiolated polymer is depicted in
Formula 7.

##STR00021##

[0060]In Formula 7, m is 0 or 1; n is 0 to 10; p is 0 or 1; o is 0 to 10,
R1, R2, R5, R6 is each individually hydrogen, a
C1-6 alkyl group, a diazeniumdiolate, if m or p is 0. R3,
R4, R7 R8 is individually hydrogen or a diazeniumdiolate,
if m or p is 1 and wherein at least one of R1-8 must be a
diazeniumdiolate;

[0061]In order to facilitate the diazeniumdiolation of the polymers,
sufficiently acidic protons, such as, but not limited to those of acetyl
groups, may be incorporated into the polymers. The functional groups that
increase the acidity of the carbon bonded protons in the polymers
include, but are not limited to, ketones, sulfones, esters, nitriles,
electron withdrawing aryl groups, nitrates, and sulfoxides. The bases
used to generate the carbanion include, but are not limited to, potassium
methoxide, sodium methoxide, cesium methoxide, lithium methoxide,
potassium ethoxide, sodium ethoxide, cesium ethoxide, lithium ethoxide,
potassium hydroxide, sodium hydroxide, cesium hydroxide, lithium
hydroxide and sodium trimethylsilanolate.

[0062]The monomers are either commercially available or synthesized with
well known synthetic transformations. For example, cyclohexanone
derivatives are treated with peroxides to form lactones (through
Baeyer-Villiger oxidation reactions) that are then used as monomers in
polymerization reactions. Other cyclic ketones and cyclic ketone
derivatives that are used for the syntheses of lactone monomers include,
but are not limited to, carbocyclic ketones having 3 to 12 ring carbons,
single and multiple substituted carbocyclic ketones having 3 to 12 ring
carbons, heterocyclic ketones having 3 to 12 ring carbons, and single and
multiple substituted heterocyclic ketones having 3 to 12 ring carbons.
The substituents on the rings include, but are not limited to substituted
or un-substituted aryl groups having 6 to 12 carbons, hydrocarbons having
at least 1 carbon, hydrocarbons bearing acidifying groups, aryl groups
bearing acidifying groups, and heteroatom substituted aryl and
hydrocarbon substituents. The heteroatoms incorporated in the
heterocycles described above include, but are not limited to nitrogen,
phosphorus, sulfur, and oxygen.

[0063]In one embodiment 2-acetylbutyrolactone is polymerized with lactide
in a diol initiated ring-opening polymerization reaction to produce the
polymer of Formula 8. These monomers are polymerized, in a non-limiting
example, in the presence of a catalyst such as, but not limited to
tin(II)-ethylhexanoate, tetrakis Sn (IV) alkoxides, cyclic tin alkoxides,
aluminum isopropoxide, zinc lactate, zinc octoate, zinc stearate, zinc
salicylate, other organic metallic compounds also used as catalysts such
as guanidinium acetate, organolanthanide, enzyme catalysts such as
lipase. The diols include, but are not limited to PEG. The polymer
represented by Formula 8 can be diazeniumdiolated as described herein.

##STR00022##

[0064]In one embodiment, the a and b units of Formula 8 are individually
integers ranging from 1 to 20,000. In additional embodiments, a is an
integer ranging from 10 to 20,000; from 50 to 15,000; from 100 to 10,000;
from 200 to 5,000; from 500 to 4,000; from 700 to 3,000; or from 1000 to
2000. In additional embodiments, b is an integer ranging from 10 to
20,000; from 50 to 15,000; from 100 to 10,000; from 200 to 5,000; from
500 to 4,000; from 700 to 3,000; or from 1000 to 2000.

[0065]The polymer of Formula 8 is diazeniumdiolated to form the polymer of
Formula 8a wherein A1-5 represent positions on the alpha carbons
that can be diazeniumdiolated and wherein a is an integer from 1 to about
20,000; b is an integer from about 1 to about 100 and the sum of a and b
is at least 2. At least one of A1-5 must be diazeniumdiolated.

##STR00023##

[0066]In another embodiment, C-based NO-donating polymers having
2-acetylbutyrolactone and glycolide monomers are produced. An exemplary
polymer, produced with these monomers, has the general structure of
Formula 9:

##STR00024##

[0067]In one embodiment, the a and b units of Formula 9 are integers
ranging from 1 to 20,000. In additional embodiments, a is an integer
ranging from 10 to 20,000; from 50 to 15,000; from 100 to 10,000; from
200 to 5,000; from 500 to 4,000; from 700 to 3,000; or from 1000 to 2000.
In additional embodiments, b is an integer ranging from 10 to 20,000;
from 50 to 15,000; from 100 to 10,000; from 200 to 5,000; from 500 to
4,000; from 700 to 3,000; or from 1000 to 2000.

##STR00025##

[0068]The polymer of Formula 9 is diazeniumdiolated to form the polymer of
Formula 9a wherein A1-6 represent positions on the alpha carbons
that can be diazeniumdiolated and wherein a is an integer from 1 to about
20,000; b is an integer from about 1 to about 100 and the sum of a and b
is at least 2. At least one of A1-6 must be diazeniumdiolated.

[0069]In another embodiment, a C-based NO-donating homopolymer comprising
the monomer 2-acetylbutyrolactone is produced. An exemplary polymer
produced with 2-acetylbutyrolactone has the general structure of Formula
10:

##STR00026##

[0070]In one embodiment, the a units of Formula 10 are integers ranging
from 1 to 20,000. In additional embodiments, a is an integer ranging from
10 to 20,000; from 50 to 15,000; from 100 to 10,000; from 200 to 5,000;
from 500 to 4,000; from 700 to 3,000; or from 1000 to 2000.

[0071]The polymer of Formula 10 is diazeniumdiolated to form the polymer
of Formula 10a wherein A1-4 represent positions on the alpha carbon
that can be diazeniumdiolated and wherein a is an integer from 1 to about
20,000. At least one of A1-4 must be diazeniumdiolated.

##STR00027##

[0072]Other acetyl-bearing monomers can be synthesized and, subsequently,
polymerized, into the polymers. In one embodiment, Baeyer-Villager
reactions are used to produce lactones with ring sizes ranging from 4 to
12 carbons. These lactones are then polymerized through ring-opening
polymerization reactions producing C-based NO-donating polymers. In one
embodiment a Baeyer-Villager reaction is initiated with
2-acetylcyclohexanone to produce the caprolactone of Formula 10.

##STR00028##

[0073]In one embodiment, a C-based NO-donating polymer is synthesized by
polymerizing 2-acetylcaprolactone with lactide in a diol-initiated
ring-opening polymerization reaction to produce the polymer of Formula
11. These monomers are polymerized in the presence of a catalyst such as
tin(II)-ethylhexanoate and a diol such as PEG.

##STR00029##

[0074]In one embodiment, the a and b units of Formula 11 are integers
ranging from 1 to 20,000. In additional embodiments, a is an integer
ranging from 10 to 20,000; from 50 to 15,000; from 100 to 10,000; from
200 to 5,000; from 500 to 4,000; from 700 to 3,000; or from 1000 to 2000.
In additional embodiments, b is an integer ranging from 10 to 20,000;
from 50 to 15,000; from 100 to 10,000; from 200 to 5,000; from 500 to
4,000; from 700 to 3,000; or from 1000 to 2000.

[0075]The polymer of Formula 11 is diazeniumdiolated to form the polymer
of Formula 11a wherein A1-5 represent positions on the alpha carbons
that can be diazeniumdiolated and wherein a is an integer from 1 to about
20,000; b is an integer from about 1 to about 100 and the sum of a and b
is at least 2. At least one of A1-5 must be diazeniumdiolated.

##STR00030##

[0076]In another embodiment, a C-based NO-donating homopolymer comprising
the monomer 2-acetylcaprolactone is produced. An exemplary polymer
produced with 2-acetylcaprolactone has the general structure of Formula
12:

##STR00031##

[0077]In one embodiment, the a units of Formula 12 are integers ranging
from 1 to 20,000. In additional embodiments, a is an integer ranging from
10 to 20,000; from 50 to 15,000; from 100 to 10,000; from 200 to 5,000;
from 500 to 4,000; from 700 to 3,000; or from 1000 to 2000.

[0078]The polymer of Formula 12 is diazeniumdiolated to form the polymer
of Formula 12a wherein A1-4 represent positions on the alpha carbon
that can be diazeniumdiolated and wherein a is an integer from 1 to about
20,000. At least one of the A1-4 must be diazeniumdiolated.

##STR00032##

[0079]In another embodiment, a C-based NO-donating polymer having monomers
comprising 2-acetylcaprolactone and glycolide is produced. An exemplary
polymer produced with these monomers has the general structure of Formula
13:

##STR00033##

[0080]In one embodiment, the a and b units of Formula 13 are integers
ranging from 1 to 20,000. In additional embodiments, a is an integer
ranging from 10 to 20,000; from 50 to 15,000; from 100 to 10,000; from
200 to 5,000; from 500 to 4,000; from 700 to 3,000; or from 1000 to 2000.
In additional embodiments, b is an integer ranging from 10 to 20,000;
from 50 to 15,000; from 100 to 10,000; from 200 to 5,000; from 500 to
4,000; from 700 to 3,000; or from 1000 to 2000.

[0081]The polymer of Formula 13 is diazeniumdiolated to form the polymer
of Formula 13a wherein A1-6 represent positions on the alpha carbons
that can be diazeniumdiolated and wherein a is an integer from 1 to about
20,000; b is an integer from about 1 to about 100 and the sum of a and b
is at least 2. At least one of the A1-6 must be diazeniumdiolated.

##STR00034##

[0082]The properties of bioabsorbable C-based NO-donating polymers are a
result of the monomers used and the reaction conditions employed in their
synthesis including, but not limited to, temperature, solvent choice,
reaction time and catalyst choice.

[0083]Varying the monomer ratios allows the ordinarily skilled artisan to
fine tune, or to modify, the properties of the polymer. The properties of
bioabsorbable C-based NO-donating polymers arise from the monomers used
and the reaction conditions employed in their synthesis including but not
limited to, temperature, solvents, reaction time and catalyst choice.

[0084]Fine tuning, or modifying, the glass transition temperature
(Tg) of the bioabsorbable C-based NO-donating polymers is also taken
into account. Drug elution from polymers depends on many factors
including density, the drug to be eluted, molecular composition of the
polymer and Tg. Higher Tgs, for example temperatures above
40° C., result in more brittle polymers while lower Tgs, e.g.
lower than 40° C., result in more pliable and elastic polymers at
higher temperatures. Drug elution is slow from polymers that have high
Tgs while faster rates of drug elution are observed with polymers
possessing low Tgs. In one embodiment, the Tg of the polymer is
selected to be lower than 37° C.

[0085]In one embodiment, the polymers can be used to form and coat medical
devices. Coating polymers having relatively high Tgs can result in
medical devices with unsuitable drug eluting properties as well as
unwanted brittleness. In the cases of polymer-coated vascular stents, a
relatively low Tg in the coating polymer effects the deployment of
the vascular stent. For example, polymer coatings with low Tgs are
"sticky" and adhere to the balloon used to expand the vascular stent
during deployment, causing problems with the deployment of the stent. Low
Tg polymers, however, have beneficial features in that polymers
having low Tgs are more elastic at a given temperature than polymers
having higher Tgs. Expanding and contracting a polymer-coated
vascular stent mechanically stresses the coating. If the coating is too
brittle, i.e. has a relatively high Tg, then fractures may result in
the coating possibly rendering the coating inoperable. If the coating is
elastic, i.e. has a relatively low Tg, then the stresses experienced
by the coating are less likely to mechanically alter the structural
integrity of the coating. Therefore, the Tgs of the polymers can be
fine tuned for appropriate coating applications by a combination of
monomer composition and synthesis conditions. The polymers are engineered
to have adjustable physical properties enabling the practitioner to
choose the appropriate polymer for the function desired.

[0086]In order to tune, or modify, the polymers, a variety of properties
are considered including, but not limited to, Tg, connectivity,
molecular weight and thermal properties.

[0087]The C-based NO-donating polymers donate NO once exposed to a
physiological environment. The rates of NO release from the polymers can
be fine tuned by selecting the appropriate monomer ratios and
diazeniumdiolate positive counterions.

[0088]Medical devices, including implantable medical devices, are
fabricated and/or coated with the polymers disclosed herein and therefore
the physical properties of the polymers are considered in light of the
specific application at hand. Physical properties of the polymers can be
fine tuned so that the polymers can optimally perform for their intended
use. Properties that can be fine tuned, without limitation, include
Tg, molecular weight (both Mn and Mw), polydispersity
index (PDI, the quotient of Mw/Mn), degree of elasticity and
degree of amphiphlicity. In one embodiment, the Tg of the polymers
range from about -10° C. to about 85° C. In still another
embodiment, the PDI of the polymers range from about 1.35 to about 4. In
another embodiment, the Tg of the polymers ranges form about
0° C. to about 40° C. In still another embodiment, the PDI
of the polymers range from about 1.5 to about 2.5.

[0090]The polymeric coatings are intended for medical devices deployed in
a hemodynamic environment and possess excellent adhesive properties. That
is, the coating must be stably linked to the medical device surface. Many
different materials can be used to fabricate the implantable medical
devices including, but not limited to, stainless steel, nitinol,
aluminum, chromium, titanium, gold, cobalt, ceramics, and a wide range of
synthetic polymeric and natural materials including, but not limited to,
collagen, fibrin and plant fibers. All of these materials, and others,
may be used with the polymeric coatings described herein. Furthermore,
the polymers can be used to fabricate an entire medical device.

[0091]There are many theories that attempt to explain, or contribute to
our understanding of how polymers adhere to surfaces. The most important
forces include electrostatic and hydrogen bonding. However, other factors
including wettability, absorption and resiliency also determine how well
a polymer will adhere to different surfaces. Therefore, polymer base
coats, or primers are often used in order to create a more uniform
coating surface.

[0092]The C-based NO donating polymeric coatings can be applied to medical
device surfaces, either primed or bare, in any manner known to those
skilled in the art. Applications methods include, but are not limited to,
spraying, dipping, brushing, vacuum-deposition, electrostatic spray
coating, plasma coating, spin coating electrochemical coating, and
others.

[0093]Moreover, the C-based NO-donating polymeric coatings may be used
with a cap coat. A cap coat as used herein refers to the outermost
coating layer applied over another coating. A C-based NO-donating polymer
coating is applied over the primer coat. Then, a polymer cap coat is
applied over the NO donating polymeric coating. The cap coat may
optionally serve as a diffusion barrier to control NO release. The cap
coat may be merely a biocompatible polymer applied to the surface of the
sent to protect the stent and have no effect on NO release rates.

[0094]The C-based NO-donating polymers are also useful for the delivery
and controlled release of drugs. Drugs that are suitable for release from
the polymers include, but are not limited to, anti-proliferative
compounds, cytostatic compounds, toxic compounds, anti-inflammatory
compounds, chemotherapeutic agents, analgesics, antibiotics, protease
inhibitors, statins, nucleic acids, polypeptides, growth factors and
delivery vectors including recombinant micro-organisms, liposomes, and
the like.

[0095]In one embodiment, the drugs controllably released include, but are
not limited to, macrolide antibiotics including FKBP-12 binding agents.
Exemplary drugs of this class include sirolimus (rapamycin), tacrolimus
(FK506), everolimus (certican or RAD-001), temsirolimus (CCI-779 or
amorphous rapamycin 42-ester with
3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid as disclosed in U.S.
patent application Ser. No. 10/930,487) and zotarolimus (ABT-578; see
U.S. Pat. Nos. 6,015,815 and 6,329,386). Additionally, other rapamycin
hydroxyesters as disclosed in U.S. Pat. No. 5,362,718 may be used in
combination with the polymers. The entire contents of all of preceding
patents and patent applications are herein incorporated by reference for
all they teach related to FKBP-12 binding compounds and the derivatives.

EXAMPLES

[0096]The following non limiting examples provide methods for the
synthesis of exemplary polymers according to the teachings of the present
invention.

Example 1

Synthesis of a Polymer of Formula 8

[0097]To a reaction vessel is added polyethylene glycol (PEG) with
molecular weight of about 3500 (1.3 g, about 0.4 mmol),
2-acetylbutyrolactone (19 g, 150 mmol), dl lactide (35 g, 243 mmol) and
tin(II)2-ethylhexanoate (0.05 g, 0.1 mmol). The vessel is purged with
nitrogen gas. The mixture is heated (150° C.) and stirred (320
rpm) for 24 hours then cooled to ambient temperature. The polymer is
discharged and dissolved in chloroform (2000 mL). Methanol (500 mL) is
added precipitating the polymer from solution. The solution is filtered
and the mother liquor disregarded. The solid polymers are then
re-dissolved in chloroform and poured into Teflon trays.

Example 2

Synthesis of a Polymer of Formula 8a

[0098]Polymers dissolved (typically 10 mg/50 ml) in THF are placed in a
high pressure reaction vessel. An inert gas (including, but not limited
to, argon and nitrogen) is then purged through the vessel. A base
dissolved in a solvent (typically sodium methoxide or potassium methoxide
in methanol) are then added in excess (typically 110% to 200%). The
reaction is allowed to stir and the vessel purged with NO gas. The
pressure of NO gas is increased (typically at least 15 psi) and the
reaction mixture is then stirred further for at least 24 hours. At the
end of the required time for the formation of diazeniumdiolates, dry
hydrophobic solvents (typically hexanes or methyl tert-butyl ether) are
added to aid in the precipitation of the polymers. The polymers are then
filtered and dried.

Example 3

Formation of Diazeniumdiolates

[0099]Polymers dissolved (typically 10 mg/50 mL) in THF are placed in a
high pressure reaction vessel. At this step, one or more bioactive agents
may be included in the polymer solution. An inert gas (including, but not
limited to, argon and nitrogen) is then purged through the vessel. A base
dissolved in a solvent (typically sodium methoxide or potassium methoxide
in methanol) are then added in excess (typically 110% to 200%). The
reaction is allowed to stir and the vessel purged with NO gas. The
pressure of NO gas is increased (typically at least 15 psi) and the
reaction mixture is then stirred further for at least 24 hours. At the
end of the required time for the formation of diazeniumdiolates, dry
hydrophobic solvents (typically hexanes or methyl tert-butyl ether) are
added to aid in the precipitation of the polymers. The polymers are then
filtered and dried.

Example 4

Manufacturing Implantable Vascular Stents

[0100]For exemplary, non-limiting, purposes a vascular stent will be
described. A bioabsorbable NO-donating polymer is heated until molten in
the barrel of an injection molding machine and forced into a stent mold
under pressure. After the molded polymer (which now resembles and is a
stent) is cooled and solidified the stent is removed from the mold. In
one embodiment the stent is a tubular shaped member having first and
second ends and a walled surface disposed between the first and second
ends. The walls are composed of extruded polymer monofilaments woven into
a braid-like embodiment. In the second embodiment, the stent is injection
molded or extruded. Fenestrations are molded, laser cut, die cut, or
machined in the wall of the tube. In the braided stent embodiment
monofilaments are fabricated from polymer materials that have been
pelletized then dried. The dried polymer pellets are then extruded
forming a coarse monofilament which is quenched. The extruded and
quenched, crude monofilament is then drawn into a final monofilament with
an average diameter from approximately 0.01 mm to 0.6 mm, preferably
between approximately 0.05 mm and 0.15 mm. Approximately 10 to 50 of the
final monofilaments are then woven in a plaited fashion with a braid
angle about 90 to 170 degrees on a braid mandrel sized appropriately for
the application. The plaited stent is then removed from the braid mandrel
and disposed onto an annealing mandrel having an outer diameter of equal
to or less than the braid mandrel diameter and annealed at a temperature
between about the polymer glass transition temperature and the melting
temperature of the polymer blend for a time period between about five
minutes and about 18 hours in air, an inert atmosphere or under vacuum.
The stent is then allowed to cool and is then cut.

Example 5

Coating Implantable Vascular Stents

[0101]A 1% solution of a bioabsorbable NO-donating polymer (such as from
Example 2) and optionally a bioactive agent such as ABT-578 (in one
embodiment in a polymer:drug ratio of 70:30 by weight), in chloroform is
sprayed on a vascular stent and allowed to dry producing a controlled
release coating on the vascular stent. Next the solubilized polymer (with
or without added bioactive agents) is applied to the surfaces of an
implantable medical device using methods known to those skilled in the
art such as, but not limited to, rolling, dipping, spraying and painting.
Excess polymer is removed under a gentle stream of warm inert gas such
as, but not limited to argon or dry nitrogen. The release of drug from
the stent into a solvent is measured by high performance liquid
chromatography (HPLC).

Example 6

Formation of Diazeniumdiolates on Polymer-Coated Vascular Stents

[0102]A vascular stent coated with at least one polymer from Example 1 is
placed in a 13 mm×100 mm glass test tube. Ten milliliters of 3%
sodium methoxide in methanol or acetonitrile is added to the test tube,
which is then placed in a 250 mL stainless steel Parr® apparatus. The
apparatus is degassed by repeated cycles (×10) of
pressurization/depressurization with nitrogen gas at 10 atmospheres.
Next, the vessel undergoes 2 cycles of pressurization/depressurization
with NO at 30 atmospheres. Finally, the vessel is filled with NO at 30
atmospheres and left at room temperature for 24 hrs. After 24 hrs, the
vessel is purged of NO and pressurized/depressurized with repeated cycles
(×10) of nitrogen gas at 10 atmospheres. The test tube is removed
from the vessel and the 3% sodium methoxide solution is decanted. The
stent is then washed with 10 mL of methanol (×1) and 10 mL of
diethyl ether (×3). The stent is then removed from the test tube
and dried under a stream of nitrogen gas. This procedure results in a
NO-donating polymer-coated vascular stent.

[0103]For exemplary, non-limiting, purposes a vascular stent will be
described. A bioabsorbable C-based NO-donating polymer is heated until
molten in the barrel of an injection molding machine and forced into a
stent mold under pressure. After the molded polymer (which now resembles
and is a stent) is cooled and solidified the stent is removed from the
mold. In one embodiment the stent is a tubular shaped member having first
and second ends and a walled surface disposed between the first and
second ends. The walls are composed of extruded polymer monofilaments
woven into a braid-like embodiment. In the second embodiment, the stent
is injection molded or extruded. Fenestrations are molded, laser cut, die
cut, or machined in the wall of the tube. In the braided stent embodiment
monofilaments are fabricated from polymer materials that have been
pelletized then dried. The dried polymer pellets are then extruded
forming a coarse monofilament which is quenched. The extruded and
quenched, crude monofilament is then drawn into a final monofilament with
an average diameter from approximately 0.01 mm to 0.6 mm, preferably
between approximately 0.05 mm and 0.15 mm. Approximately 10 to 50 of the
final monofilaments are then woven in a plaited fashion with a braid
angle about 90 to 170 degrees on a braid mandrel sized appropriately for
the application. The plaited stent is then removed from the braid mandrel
and disposed onto an annealing mandrel having an outer diameter of equal
to or less than the braid mandrel diameter and annealed at a temperature
between about the polymer glass transition temperature and the melting
temperature of the polymer blend for a time period between about five
minutes and about 18 hours in air, an inert atmosphere or under vacuum.
The stent is then allowed to cool and is then cut.

[0104]Unless otherwise indicated, all numbers expressing quantities of
ingredients, properties such as molecular weight, reaction conditions,
and so forth used in the specification and claims are to be understood as
being modified in all instances by the term "about." Accordingly, unless
indicated to the contrary, the numerical parameters set forth in the
following specification and attached claims are approximations that may
vary depending upon the desired properties sought to be obtained by the
present invention. At the very least, and not as an attempt to limit the
application of the doctrine of equivalents to the scope of the claims,
each numerical parameter should at least be construed in light of the
number of reported significant digits and by applying ordinary rounding
techniques. Notwithstanding that the numerical ranges and parameters
setting forth the broad scope of the invention are approximations, the
numerical values set forth in the specific examples are reported as
precisely as possible. Any numerical value, however, inherently contains
certain errors necessarily resulting from the standard deviation found in
their respective testing measurements.

[0105]The terms "a," "an," "the" and similar referents used in the context
of describing the invention (especially in the context of the following
claims) are to be construed to cover both the singular and the plural,
unless otherwise indicated herein or clearly contradicted by context.
Recitation of ranges of values herein is merely intended to serve as a
shorthand method of referring individually to each separate value falling
within the range. Unless otherwise indicated herein, each individual
value is incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in any
suitable order unless otherwise indicated herein or otherwise clearly
contradicted by context. The use of any and all examples, or exemplary
language (e.g. "such as") provided herein is intended merely to better
illuminate the invention and does not pose a limitation on the scope of
the invention otherwise claimed. No language in the specification should
be construed as indicating any non-claimed element essential to the
practice of the invention.

[0106]Groupings of alternative elements or embodiments of the invention
disclosed herein are not to be construed as limitations. Each group
member may be referred to and claimed individually or in any combination
with other members of the group or other elements found herein. It is
anticipated that one or more members of a group may be included in, or
deleted from, a group for reasons of convenience and/or patentability.
When any such inclusion or deletion occurs, the specification is deemed
to contain the group as modified thus fulfilling the written description
of all Markush groups used in the appended claims.

[0107]Certain embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on those embodiments will become
apparent to those of ordinary skill in the art upon reading the foregoing
description. The inventor expects skilled artisans to employ such
variations as appropriate, and the inventors intend for the invention to
be practiced otherwise than specifically described herein. Accordingly,
this invention includes all modifications and equivalents of the subject
matter recited in the claims appended hereto as permitted by applicable
law. Moreover, any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by context.

[0108]Furthermore, numerous references have been made to patents and
printed publications throughout this specification. Each of the above
cited references and printed publications are individually incorporated
by reference herein in their entirety.

[0109]In closing, it is to be understood that the embodiments of the
invention disclosed herein are illustrative of the principles of the
present invention. Other modifications that may be employed are within
the scope of the invention. Thus, by way of example, but not of
limitation, alternative configurations of the present invention may be
utilized in accordance with the teachings herein. Accordingly, the
present invention is not limited to that precisely as shown and
described.